Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Comparative Proteomics Elucidates the Potential Mechanism of Sperm Capacitation of Chinese Mitten Crabs (Eriocheir sinensis).

Sperm capacitation is broadly defined as a suite of biochemical and biophysical changes resulting from the acquisition of fertilization ability. To gain insights into the regulation mechanism of crustacean sperm capacitation, 4D label-free quantitative proteomics was first applied to analyze the changes of sperm in Eriocheir sinensis under three sequential physiological conditions: seminal vesicles (X2), hatched with the seminal receptacle content (X3), and incubated with egg water (X5). In total, 1536 proteins were identified, among which 880 proteins were quantified, with 82 and 224 proteins significantly altered after incubation with the seminal receptacle contents and egg water. Most differentially expressed proteins were attributed to biological processes by Gene Ontology annotation analysis. As the fundamental bioenergetic metabolism of sperm, the oxidative phosphorylation, glycolysis, and the pentose phosphate pathway presented significant changes under the treatment of seminal receptacle contents, indicating intensive regulation for sperm in the seminal receptacle. Additionally, the seminal receptacle contents also significantly increased the oxidation level of sperm, whereas the enhancement of abundance in superoxide dismutase, peroxiredoxin 1, and glutathione S-transferase after incubation with egg water significantly improved the resistance against oxidation. These results provided a new perspective for reproduction studies in crustaceans.

Interaction between activities of daily living and cognitive function on risk of depression.

Objective: There is a lack of literature about the joint effects of activities of daily living (ADL) limitation and cognitive impairment on depression. This study aimed to estimate the association of ADL limitation and cognitive impairment with depression among Chinese older adults aged 65 and above and to test their interaction on both additive and multiplicative scales. Methods: Data was drawn from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), including 11,025 eligible participants. Logistic regression models were fitted, and both multiplicative and additive interactions for ADL limitation and cognitive impairment were tested. Results: A total of 3,019(27.4%) participants reported depressive symptoms. After controlling for potential confounding factors, ADL limitation and cognitive impairment were both positively associated with depression. The adjusted additive interaction of basic and instrumental activities of daily living limitation were 2.47 (95%CI:1.92-3.19) and 3.67 (95%CI:2.88-4.66), respectively, but the multiplicative interaction items were both insignificant. Conclusion: ADL limitation and cognitive impairment were both risk factors for depression among Chinese older adults. Moreover, the significant interaction of ADL limitation and cognitive impairment was found in the additive model, suggesting that improving ADL may be helpful in reducing the risk of depression among older people with cognitive impairment.

Time trends in the burden of autoimmune diseases across the BRICS: an age-period-cohort analysis for the GBD 2019.

BACKGROUND: This study aims to evaluate the long-term trend of prevalence and DALY (disability-adjusted life-year) rate on the age, period and cohort (APC) of the BRICS (Brazil, Russia, India, China and South Africa) country for autoimmune diseases (rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS) and psoriasis). METHODS: The data are sourced from the Global Burden of Disease Study 2019, and it uses the Joinpoint regression model to estimate the time trends of autoimmune diseases from 1990 to 2019. Additionally, it employs the Age-Period-Cohort (APC) model to estimate the age, period, and cohort effects from 1990 to 2019. RESULTS: For 1990 to 2019, the ASPR (age-standardised prevalence rate) of IBD increased significantly for China and South Africa, and decreased significantly for Brazil, India, Russian. The Russian ASPR of MS demonstrated a significantly decreasing trend (average annual percent change=-0.5%, 95% CI -0.6 to -0.5), with the most increased occurring in Brazil at 2009-2014. The cohort effect on DALY rates for Psoriasis displayed an ongoing decreasing trend from the 1929-1933 birth cohort to the 1999-2003 birth cohort. Specifically, the five countries relative risk values (RRs) of DALYs due to RA increased significantly by 7.98, 16.07, 5.98, 3.19, 9.13 times, from 20 to 24 age group to 65 to 69 age group. CONCLUSIONS: The population of the BRICS countries accounts for more than 40% of the global population. And we found that the age effect of various autoimmune diseases is heavily influenced by population ageing.

Sperm acrosomal released proteome reveals MDH and VDAC3 from mitochondria are involved in acrosome formation during spermatogenesis in Eriocheir sinensis.

Acrosome is inextricably related to membranous organelles. The origin of acrosome is still controversial, one reason is that limited articles were reported about the proteomic analysis of the acrosome. Mitochondrial proteins were found exist in the acrosome, nevertheless, only limited attention has been paid to the function of mitochondrial proteins in the acrosome formation. Eriocheir sinensis sperm has a large acrosome, which makes it an ideal model to study acrosome formation. Here, we firstly compared the rate of acrosome reaction induced by the calcium ionophore A23187 and ionomycin. The rate of acrosome reaction induced by ionomycin is higher (95.8%) than A23187 (58.7%). Morphological changes were observed using light, confocal and transmission electron microscopy. Further more, proteins released during the acrosome reaction as induced by ionomycin were collected for LC-MS/MS analysis. A total of 945 proteins, including malate dehydrogenase (MDH) and voltage-dependent anion channel 3 (VDAC3), were identified in the acrosomal released proteome. The number of proteins from mitochondria (17.57%) was higher compared with endoplasmic reituculum (1.59%) and lysosomes (1.8%). To investigate the functions of target mitochondrial proteins during spermatogenesis, poly-antibodies of MDH in E. sinensis were prepared. The characteristics, further analyzed using immunofluorescence, of two mitochondrial proteins during acrosome formation showed that MDH and VDAC3 were independently involved in the formation of acrosomal membrane. These findings illustrate the acrosomal released proteome and provide important data resource for understanding the relationship between mitochondria and the acrosome in Decapoda crustacean.

Microsatellite markers reveal genetic diversity and population structure of Portunus trituberculatus in the Bohai Sea, China.

The swimming crab, Portunus trituberculatus, is one of the main aquaculture species in Chinese coastal regions due to its palatability and high economic value. To obtain a better understanding of the genetic diversity of P. trituberculatus in the Bohai Sea, the present study used 40 SSR loci to investigate the genetic diversity and population structure of 420 P. trituberculatus individuals collected from seven populations in the Bohai Sea. Genetic parameters revealed a low level of genetic diversity in the cultured population (SI = 1.374, He = 0.687, and PIC = 0.643) in comparison with wild populations (SI ≥ 1.399, He ≥ 0.692, and PIC ≥ 0.651). The genetic differentiation index (Fst) and gene flow (Nm) ranged from 0.001 to 0.060 (mean: 0.022) and 3.917 to 249.750 (mean: 31.289) respectively, showing a low differentiation among the seven populations of P. trituberculatus. Population structure analysis, phylogenetic tree, and principal component analysis (PCA) demonstrated that the seven groups of P. trituberculatus were divided into four subpopulations (K = 4), but the correlation between genetic structure and geographical distribution was not obvious. These results are expected to provide useful information for the fishery management of wild swimming crabs.

The efficacy of mindfulness-based stress reduction vs. standard or usual care in patients with breast cancer: a systematic review and meta-analysis of randomized controlled trials.

Background: Mindfulness-based stress reduction (MBSR) has become an alternative intervention for cancer patients, but its impact on depression and quality of life (QOL) of breast cancer patients remains controversial. The aim of this study was to evaluate the effects of MBSR vs. standard or usual care to relieve psychological stress in patients with breast cancer. Methods: According to the PICOS principles, databases [PubMed, Cochrane Database, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), China Scientific Journal Database (VIP), and Wanfang Database] were searched for randomized controlled trials (RCTs) on the evaluation of MBSR vs. standard or usual care for patients with breast cancer, the outcome variables included depression, stress, anxiety, fatigue, sleep and QOL. Review Manager 5.4 was used to evaluate the effects of the results among selected articles. Forest plots and funnel plots were also performed. The risk of bias was assessed using the Cochrane Risk of Bias Tool. Results: The final analysis included 14 studies with a total of 2,224 patients (1,138 in the MBSR group and 1,086 in the control group). The overall results of risk of bias assessment showed that the reporting bias among articles was high, and other bias was relatively moderate. Funnel plots and Egger's tests showed that there was no significant publication bias. Compared with standard or usual care, MBSR effectively relieved the psychological stress [mean difference (MD), -1.72; 95% confidence interval (CI): (-2.53, -0.92); P<0.0001] and anxiety [standardized mean difference (SMD), -1.36; 95% CI: (-2.13, -0.60); P=0.0005] of breast cancer patients, and improved depression [SMD, -0.62; 95% CI: (-1.20, -0.03); P=0.04] and sleep status [MD, -0.42; 95% CI: (-0.73, -0.10), P=0.009]. However, it had no significant effect on fatigue [SMD, -0.97; 95% CI: (-2.24, 0.31); P=0.14] or QOL [MD, 1.95; 95% CI: (-3.15, 7.05); P=0.45]. Conclusions: MBSR was better than standard or usual care for relieving psychological stress, anxiety, depression, and sleep in patients with breast cancer. Considering the limitations of this article, such as high risk of bias and high heterogeneity of included studies, the interpretation of this conclusion should be cautious.

Comprehensive Analysis of HMCN1 Somatic Mutation in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a common malignancy of the genitourinary system and clear cell renal cell carcinoma (ccRCC) is the most representative subtype. The morbidity and mortality of ccRCC have gradually risen during recent years; however, the pathogenesis and potential biomarkers remain unclear. The purpose of our study was to find out prognostic genes correlated with somatic mutation and the underlying mechanisms of HMCN1 mutation in ccRCC. METHODS: Somatic mutation data of two ccRCC cohorts were acquired from TCGA and cBioPortal. Genes frequently mutated in both datasets were extracted, from which tumor mutation burden and survival analysis revealed three prognostic genes. Further comprehensive analysis of HMCN1 mutation was carried out to identify differentially expressed genes and apply functional annotations. The correlation of HMCN1 mutation and tumor immunity was also evaluated. RESULTS: HMCN1, SYNE1, and BAP1 mutations were associated with both tumor mutation burden and clinical prognosis in ccRCC. Gene enrichment analysis suggested the effects of HMCN1 mutation on biological processes and pathways linked to energy metabolism. HMCN1 mutation was also correlated with anti-tumor immunity. There were several limitations in the sample size and cohort availability of the present computational study. CONCLUSIONS: The present results inferred that HMCN1 mutation might have an important clinical significance for ccRCC patients by regulating metabolism and the immune microenvironment.

FMRP ligand circZNF609 destabilizes RAC1 mRNA to reduce metastasis in acral melanoma and cutaneous melanoma.

BACKGROUND: Melanoma is a type of malignant tumor with high aggressiveness and poor prognosis. At present, metastasis of melanoma is still an important cause of death in melanoma patients. However, the potential functions and molecular mechanisms of most circular RNAs (circRNAs) in melanoma metastasis remain unknown. METHODS: circRNAs dysregulated in melanoma cell subgroups with different metastatic abilities according to a screening model based on repeated Transwell assays were identified with a circRNA array. The expression and prognostic significance of circZNF609 in skin cutaneous melanoma and acral melanoma cells and tissues were determined by qRT-PCR, nucleoplasmic separation assays and fluorescence in situ hybridization. In vitro wound healing, Transwell and 3D invasion assays were used to analyse melanoma cell metastasis ability. Tail vein injection and intrasplenic injection were used to study in vivo lung metastasis and liver metastasis, respectively. The mechanism of circZNF609 was further evaluated via RNA immunoprecipitation, RNA pull-down, silver staining, and immunofluorescence colocalization assays. RESULTS: circZNF609 was stably expressed at low levels in melanoma tissues and cells and was negatively correlated with Breslow depth, clinical stage and prognosis of melanoma patients. circZNF609 inhibited metastasis of acral and cutaneous melanoma in vivo and in vitro. Mechanistically, circZNF609 promoted the binding of FMRP protein and RAC1 mRNA, thereby enhancing the inhibitory effect of FMRP protein on the stability of RAC1 mRNA and ultimately inhibiting melanoma metastasis. CONCLUSIONS: Our findings revealed that circZNF609 plays a vital role in the metastasis of acral and cutaneous melanoma through the circRNF609-FMRP-RAC1 axis and indicated that circZNF609 regulates the stability of RAC1 mRNA by combining with FMRP, which might provide insight into melanoma pathogenesis and a new potential target for treatment of melanoma.

Study of SARS-CoV-2 transmission in urban environment by questionnaire and modeling for sustainable risk control.

Caused by SARS-CoV-2, COVID-19 has become a severe threaten to society and human health, its epidemic control emerges as long-term issue. A sustainable epidemic and environmental transmission risk control (SEERC) in urban area is urgently needed. This work aims to conduct a new investigation on the transmission risk of SARS-COV-2 as virus/hazardous material through various environmental medias, routes and regions in the entirely urban area for guiding the SEERC. Specifically, 5 routes in 28 regions (totally 140 scenarios) are considered. For a new perspective, the risk evaluation is conducted by the quantification of frontline medicals staffs' valuable experience in this work. 207 specialists responsible for the treatment of over 9000 infected patients are involved. The result showed that degree of risk was in the order of breath>contact-to-object>contact-to-human>intake>unknown. The modeling suggested source control as the prior measure for epidemic control. The combination of source control & mask wearing showed high efficiency in SEERC. The homeworking policy needed to cooperate with activity limitation to perform its efficiency. Subsequently, a new plan for SEERC was discussed. This work delivered significant information to researchers and decision makers for the further development of sustainable control for SARS-COV-2 spreading and COVID-19 epidemic.

Efficacy and safety of Shen-Ling-Bai-Zhu-San combined with chemotherapy for lung cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: Lung cancer (LC), with the high incidence in malignant tumors in the world, and seriously affects people's lives and brings a great economic burden. Previous clinical studies on Shen-Ling-Bai-Zhu-San (SLBZS) combined with chemotherapy for the treatment of lung cancer have been increasing, but there are no systematic reviews. This study aims to systematically study the efficacy and safety of SLBZS combined with chemotherapy in the treatment of LC. METHODS: The Chinese and English databases will be searched by us for related documents, and the search time limit is January 2021. Databases including PubMed, Embase, Web of Science, the Cochrane Library, Chinese databases include China National Knowledge Infrastructure, Wanfang Data, ChongqingVIP Information Resource Integration Service Platform, China Biomedical Literature. The international clinical trial registration platform and the Chinese clinical trial registration platform will be searched by us to find ongoing or unpublished trials. After screening the literature based on inclusion and exclusion criteria, 2 researchers independently extracted data. The primary outcomes were the treatment efficiency. RevMan 5.3.5 software will be used for statistical analysis. The Recommendation, Assessment, Development, and Evaluation (GRADE) system will be used to evaluate the quality evidence of each result. RESULTS: This study will provide the latest evidence for the SLBZS combined with chemotherapy for LC. CONCLUSION: The efficacy and safety of SLBZS combined with chemotherapy for LC will be evaluated. UNIQUE INPLASY NUMBER: INPLASY202110025.

Role of Lactobacillus in Female Infertility Via Modulating Sperm Agglutination and Immobilization.

Infertility has become a common problem in recent decades. The pathogenesis of infertility is variable, but microbiological factors account for a large proportion of it. Dysbiosis of vaginal microbiota is reportedly associated with female infertility, but the influence of normal vaginal microbiota on infertility is unclear. In this review, we summarize the physiological characteristics of the vaginal tract and vaginal microbiota communities. We mainly focus on the bacterial adherence of vaginal Lactobacillus species. Given that the adherent effect plays a crucial role in the colonization of bacteria, we hypothesize that the adherent effect of vaginal Lactobacillus may also influence the fertility of the host. We also analyze the agglutination and immobilization effects of other bacteria, especially Escherichia coli, on ejaculated spermatozoa, and speculate on the possible effects of normal vaginal microbiota on female fertility.

Role of Long Noncoding RNA 799 in the Metastasis of Cervical Cancer through Upregulation of TBL1XR1 Expression.

Long noncoding RNAs (lncRNAs) are closely associated with the molecular mechanisms underlying cancer development, and it would be highly useful to study their expression and mechanisms in cervical cancer too. The current study investigated lncRNA799 expression in cervical cancer in order to determine its clinical importance in the progression of cervical cancer. lncRNA799 expression was studied in 218 cervical cancer samples. Expression of lncRNA799 was significantly higher in the cervical cancer tissue than in the adjacent normal tissue. Overexpression of lncRNA799 was found to have a significant correlation with FIGO stage, SCC-Ag level, and lymphatic metastasis, and it was also associated with poor survival. Ectopic expression of lncRNA799 promoted the metastasis of SiHa cells, whereas lncRNA799 knockdown had an inhibitory effect on metastasis. Western blot analysis demonstrated that lncRNA799 promotes the expression of transducing ß-like protein 1-related protein (TBL1XR1), and that lncRNA799 and TBL1XR1 expression show strong correlation in cervical cancer. Moreover, lncRNA799 modulated the expression of TBL1XR1 by acting as a competitive endogenous RNA (ceRNA) for miR-454-3P. The results indicate that lncRNA799 could be used as a novel marker of cervical cancer prognosis. Thus, targeting the ceRNA network involving lncRNA799 could be a potential treatment strategy against cervical cancer.

Comparison of the common bacteria in human and mouse tumours using high-throughput sequencing.

Evidence has indicated that gut bacteria may serve an important role in cancer development and therapy, while little work has been done to explore the microbial diversity inside tumours. In the present study, high­throughput sequencing was first used to identify and compare the microbial diversity in human and mouse tumours. Principal component analysis (PCA) and ß-diversity indicated a low microbial similarity among mouse artificial tumours (M.AT group), mouse spontaneous tumours (M.T group) and human tumours (H.T group), and Serratia (35.85 vs. 32.64 vs. 73.32%), Pseudomonas (24.10 vs. 16.62 vs. 1.72%) and Ochrobactrum (6.28 vs. 11.08 vs. 11.90%) were identified as dominant bacteria at the genus level. In addition, Venn results indicated 103 common operational taxonomic units (OTUs) in the M.AT, M.T and H.T groups, and only 2 and 1 OTUs belonged to Lactobacillus and Escherichia, respectively, while no OTUs belonging to Salmonella, Bifidobacteria or Clostridium were identified. In the present study, the common bacteria between human and mouse tumours were identified, which may serve as potential strains for bacteriotherapy of cancers.